Evidence that the inhibition of luteinizing hormone secretion exerted by central administration of neuropeptide Y (NPY) in the rat is predominantly mediated by the NPY-Y5 receptor subtype

A number of studies have indicated that neuropeptide Y (NPY) is a central r egulator of the gonadotropic axis, and the Y1 receptor was initially sugges ted to be implicated. As at least five different NPY receptor subtypes have now been characterized, the aim of the present study was to reinvestigate the pharmacological profile of the receptor(s) mediating the inhibitory act ion of NPY on LH secretion by using a panel of NPY analogs with different s electivity toward the five NPY receptor subtypes. When given intracerebrove ntricularly (icv) to castrated rats, a bolus injection of native NPY (0.7-2 .3 nmol) dose-dependently decreased plasma LH. Peptide YY (PYY; 2.3 nmol) w as as potent as NPY, suggesting that the Y3 receptor is not implicated. Con firming previous data, the mixed Y1, Y4, and Y5 agonist [Leu(31),Pro(34)]NP Y (0.7-2.3 nmol) inhibited LH release with potency and efficacy equal to th ose of NPY. Neither the selective Y2 agonist CS-NPY (2.3 nmol) nor the sele ctive Y4 agonist rat pancreatic polypeptide affected plasma LH, excluding Y 2 and Y4 subtypes for the action of NPY on LH secretion. The mixed Y4-Y5 ag onist human pancreatic polypeptide (0.7-7 nmol) as well as the mixed Y2-Y5 agonist PYY3-36 (0.7-7 nmol) that displayed very low affinity for the Y1 re ceptor, thus practically representing selective Y5 agonists in this system, decreased plasma LH with potency and efficacy similar to those of NPY, ind icating that the Y5 receptor is mainly involved in this inhibitory action o f NPY on LH secretion. [D-Trp(32)]NPY, a selective, but weak, Y5 agonist, a lso inhibited plasma LH at a dose of 7 nmol. Furthermore, the inhibitory ac tion of NPY (0.7 nmol) on LH secretion could be fully prevented, in a dose- dependent manner (6-100 mu g, icy), by a nonpeptidic Y5 receptor antagonist . This antagonist (60 mu g, icy) also inhibited the stimulatory action of N PY (0.7 nmol) on food intake. The selectivity of PYY3-36, human PP, [D-Trp( 32)] NPY, and the Y5 antagonist for the Y5 receptor subtype was further con firmed by their ability to inhibit the specific [I-126] [Leu(31),Pro(34)]PW binding to rat brain membrane homogenates in the presence of the Y1 recept or antagonist BIBP3226, a binding assay system that was described as being highly specific for YS-like receptors. With the exception of [D-Trp(32)]NPY , all analogs able to inhibit LH secretion were also able to stimulate food intake. Taken together, these results indicate that the Y5 receptor is inv olved in the negative control by NPY of the gonadotropic axis.